Lamotrigine–Clozapine Combination in Refractory Schizophrenia: Three Cases
Lamotrigine (LMG) was added to clozapine (CLZ) monotherapy of 3 patients who responded poorly after more than 6 months of CLZ treatment. Lamotrigine was initiated with 25 mg/day (day 0) and gradually increased according to the clinical response. Brief Psychiatric Rating Scale (BPRS) ratings were obtained before the introduction of LMG (baseline: day 0) and then every 4 weeks during 12 weeks.
Case Reports
Patient 1. Male, 36 years old. CLZ dosage 700 mg/day. Significant decrease of BPRS score was observed from 56 (day 0) to 49 (day 28, LMG 50 mg/day) to 43 (day 56, LMG 100 mg/day) to 30 (day 84, LMG 150 mg/day). Symptom improvement and increased autonomy have allowed his discharge for the first time after several years of hospitalization. Steady-state concentrations of CLZ, norclozapine (NCLZ), and LMG in plasma were 235 ng/ml, 230 ng/ml, and 0.78 μg/ml, respectively, at day 83 (LMG 125mg/day).
Patient 2. Male, 34 years old. CLZ dosage 500 mg/day. BPRS scores decreased from 66 (baseline) to 52 (day 28, LMG 50 mg/day), 52 (day 56, LMG 75 mg/day), and 52 (day 84, LMG 75 mg/day). Steady-state concentrations of CLZ, NCLZ, and LMG in plasma were 320 ng/ml, 405 ng/ml, and 0.57 μg/ml, respectively, at day 56 (LMG 75mg/day).
Patient 3. Female, 31 years old. CLZ dosage 700mg/day. BPRS scores decreased from 43 (baseline) to 35 (day 28, LMG 75 mg/day), 32 (day 56, LMG 75 mg/day), and 31 (day 84, LMG 200 mg/day). Steady-state concentration of CLZ, NCLZ, and LMG in plasma were 590 ng/ml, 420 ng/ml, and 1.28 μg/ml, respectively, at day 85 (LMG 200 mg/day).
No marked side effects, rash, or hematological changes were observed for any of these patients.
Comment
Lamotrigine is a new antiepileptic agent acting by means of inhibition of voltage-sensitive channel sodium current.1 LMG, by inhibiting N-methyl-d-aspartate (NMDA) receptor, decreases the release of glutamate. According to Dursun,1 LMG may enhance glutamate antagonist activity of drugs such as clozapine and has showed promise in combination with clozapine treatment of refractory schizophrenia.
In our three cases, significant decrease of BPRS scores was rapidly obtained and was maintained during the 12 weeks of LMG-CLZ combination. Decreases of 47%, 22%, and 28% were achieved at day 84 for Patients 1, 2 and 3, respectively. A tentative target range for LMG concentrations has been proposed in epilepsy treatment (1–4 μg/ml). This target range has been questioned, and our observations may indicate that concentrations lower than 1 μg/ml are relevant for psychiatric indications as well.
These clinical observations indicate that rapid improvement of psychiatric symptoms may be obtained when lamotrigine is added to clozapine in cases of poor response or resistance to clozapine monotherapy. Nevertheless, controlled studies have to be carried out to determine the risk–benefit ratio of this combination.
1 Dursun SM, McIntosh D, Milliken H: Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch Gen Psychiatry 1999; 56:950-951Crossref, Medline, Google Scholar
2 Fitton A, Goa KL: Lamotrigine: update of its pharmacology and therapeutic use in epilepsia. Drugs 1995; 50:691-713Crossref, Medline, Google Scholar
